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Genetic counseling: Fanconi Anemia
Fanconi Anemia Overview *Inherited anemia leading to bone marrow failure (aplastic anemia) and myelodysplasia (5%) or acute myelogenous leukemia (10%) and physical abnormalities (60-75%), and increased risk for other cancers Associated Cancers *Acute myelogenous leukemia *Older patients risk of head and neck, esophageal, gastrointestinal, and genital tract cancers **Usually develop after 13 years of age (average age is 23) **Difficult to treat due to sensitivity to DNA-damaging agents such a chemo and radiation *Patients who receive androgen treatment are at increased risk of liver tumors Physical Characteristics/symptoms (25-40% have no physical abnormalities) *Short stature (60%) *Extreme fatigue *Frequent infections *Nosebleeds or easy bruising *Low white cell, red cell, or platelet count (age of onset highly variable) *Myelodysplasia *Upper limb malformations: misshapen, missing or extra thumbs or an incompletely developed or missing radius (50%) *Other skeletal anomalies (30%) - short low hairline, spina bifida, scoliosis, sacrococcygeal sinus, vertebral anomalies *Renal malformations (25%) pelvic, horseshoe, hypoplastic, dysplastic kidney or abnormal artery or abnormal collecting system *Abnormal skin pigmentation (café-au-lait spots, hyperpigmentation, hypopigmentation (65%) *Microcephaly *Eyes (25%) - micropthalmia, strabismus, epicanthal folds, hypertelorism/hypotelorism, ptosis, slanting, cataracts, epiphora, nystagmus *Genitalia (40%) - **males: hypogenitalia, undescended, absent or atrophic testes, azospermia, delayed puberty. Few males have fathered children **females: hypogenitalia, bicornauate uterus, absence of uterus or vagina, ovarian atresia, delayed menarche, irregular menses, early menopause. Successful pregnancies have been reported *Ears (10%) - deafness usually conductive due to middle ear anomalies, abnormal pinna, stenosis or atreasia of external auditory meatus, lowest, large or small ears *Heart structural defects, cardiomyopathy *Lower limbs-toe syndactyly, pes planus, abnormal toes, congenital hip dislocation *Mental retardation or learning disabilities *Low birth weight *Gastrointestinal problems/malformations Genetic Basis *AR inheritance *At least 8 FA genes A (16q24.3) 66%, B(?) 4%, C(9q22.3) 12%, D1 rare, D2(3p25.3) rare, E(6p21-22) 12%, F(11p15) rare, G(9p13) rare, (BRCA2 is thought to be B or D1) *FA-A and FA-C mutations account for 76% of patients *FA pathway regulates DNA repair Incidence *Found equally in males and females *All ethnic groups *1 in 100,000 live births Carrier frequency *Estimated between 1 in 600 and 1 in 100 *gene clinics states 1 in 300 for general population in US, Europe and Japan *AJ frequency is 1 in 89 Diagnosis and testing *Chromosomal breakage studies in presence of diepoxybutane (DEB) or mitomycin C (MMC) *Only FA cells exhibit increased chromosomal breakage in response to DEB *Chromosomal breakage can be performed prenatally with cells from CVS or amnio *If mutations known, mutation analysis can be performed prenatally *Chromosome breakage tests don't detect carriers *Siblings should be tested since 25-40% of individuals with FA may have no physical abnormalities *Complementation studies and mutation analysis available for 6 of the genes on research basis *Fanconi Anemia mutation database found at www.rockefeller.edu/fanconi/mutate/ *FA cell repository in Oregon (will do complementation analysis) *Carrier testing available once mutations identified Mosaicism *Some cells revert to normal phenotype *Attributed to recombination or gene conversion *May cause false negative DEB test Geneotype-Phenotype *Appear to be some correlations Differential Diagnosis *Bloom syndrome, ataxia telangiectasia, and other chromosomal breakage syndromes are all ruled out by DEB chromosomal breakage test *NF1 shares café au lait spots *Thrombocytopenia with absent radii *VACTERL syndrome *Above are ruled out by DEB or MMC test Leukemia *Malignancy where bone marrow produces excess quantities of immature white cells called blasts *These suppress the development of healthy blood cells *Results in infections and bleeding *AML is a particularly aggressive type usually found in older people Management of FA (focuses on surveillance of and treatment for physical abnormalities, bone marrow failure, and related cancers) *Baseline tests **Ultrasound of kidneys and urinary tract **Formal hearing test **Baseline developmental assessment **Referral to ophthalmologist, endocrinologist, and geneticist for initial screening and counseling **Follow by hematologist ***HLA typing of patient, sibs, and parents: full blood typing and blood chemistries ***Regular blood counts ***Many recommend annual bone marrow aspirate or biopsy to evaluate morphology, cellularity, and cytogenetics *Androgens **Improve blood counts in ~50% of patients **stimulate production of RBC's, often platelets, sometimes WBC's **patients often eventually fail to respond to this treatment *Hematopoetic growth factors **G-CSF or GM-CSF stimulate production of WBC's in some patients **Improved platelet and red cell count in a few patients **Generally not recommended for patients with a clonal cytogenetic abnormality *Blood transfusions **Should be avoided or minimized if patient is a candidate for bone marrow transplantation **Family members should be avoided as blood donors to minimize chance of sensitization if considering bone marrow transplant *Bone marrow transplant **Only long-term cure for blood problems **Many associated risks *Gene therapy **Clinical trials for patients with mutations in A or C gene **Potentially correct the hematopoietic defect, but not reduce the risk of developing solid tumors in other tissues **Not done if considering bone marrow transplant Resources *Fanconi Anemia Cell Repository :Department of Medical and Molecular Genetics :Oregon Health & Science University :3181 SW Sam Jackson Park Rd, L103 :Portland, OR 97201 :Phone: 503-494-6888 *Fanconi Anemia Research Fund, Inc (FARF) :1801 Willamette Street, Suite 200 :Eugene, OR 97401 :Phone: 800-828-4891; 541-687-4658 :Fax: 541-687-0548 :Email: info@fanconi.org :www.fanconi.org *Fanconi Anemia Mutation Registry :www.rockefeller.edu/fanconi/mutate *Cancer Fund of America :2901 Breezewood Lane, Knoxville, TN 37921-1009 :(423) 938-5281 :Supplies and financial aid for low income :cancer patients *For more resources see Fanconi Anemia: A Handbook for Families and Their Physicians, 2000 References *Gene Reviews www.geneclinics.com Fanconi anemia *Handout from presentation by Dr. Alan D'Andrea *Lynn and Dave Frohnmayer. Fanconi Anemia: A Handbook for Families and Their Physicians Third Edition, 2000 *"Biallelic Inactivation of BRCA2 in Fanconi Anemia" was published in the June 13, 2002 edition of Sciencexpress, one of the on-line versions of the journal Science. *Fanconi Anemia Research Fund www.fanconi.org Notes The information in this outline was last updated in 2003. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.